Fig. 2.

Origins of centromeric breaks. Schematic of the possible causes that lead to chromosome breaks at centromere. a Segregation errors: merotelic attachment and k-fiber accumulation are the sources of lagging chromosome formation and centromere distortion in mitosis leading to micronuclei and centromere breaks. b DNA topology: the complex DNA topology enriched in catenanes is normally resolved by topoisomerases prior to completion of sister chromatid separation. Resolution of UFBs is also crucial for maintenance of genome integrity in which a fraction of those results in 53BP1 nuclear bodies (NB) that are repaired in the next cell cycle. Alterations in the centromere decatenation pathway can lead to anaphase bridges and DNA breaks. c, d DNA replication and recombination: due to its highly repetitive sequences a non-canonical pathway of DNA damage and homologous recombination proteins is implicated in the correct completion of centromere replication in order to avoid formation of anaphase bridges, unscheduled recombination and, consequently, segregation errors and breaks